[119528-80-2]  · C29H43ClO12Ti  · Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium  · (MW 667.05)

(highly enantio- and diastereoselective aldol reactions of acetic acid,1 propionic acid,2 and glycine3 ester enolates with various aldehydes; stereoselective addition of allyl groups to aldehydes4)

Physical Data: crystal structure; 1H and 13C NMR.5

Solubility: toluene (not determined, 0.155 M possible); Et2O (not determined, 0.09 M possible).4

Analysis of Reagent Purity: 1H NMR; test reaction.

Preparative Methods: see Trichloro(cyclopentadienyl)titanium.

Handling, Storage, and Precautions: best handled as stock solution either in Et2O (ca. 0.1 M) or toluene (ca. 1.5 M), which must be protected from moisture and UV light. If handled under an inert atmosphere (argon), such solutions can be stored in a refrigerator (8 °C) for several months (possibly much longer) without deterioration. Reactions should be carried out in dry equipment and with absolute solvents under Ar or N2.

Aldol Reactions.

The titanium enolate (2) is obtained by addition of ca. 1.3 equiv of the title reagent (1) as a 0.1-0.15 M solution in toluene to the Li enolate of t-butyl acetate (3) generated at -78 °C with lithium dicyclohexylamide in Et2O. This transmetalation takes about 24 h at -78 °C but is completed within 1 h at -30 °C (eq 1).1a,b The medium might also be important, as it has recently been reported that 12-Crown-4 has to be added for reproducible results in THF-Et2O.1c The solution of (2) usually is recooled to -78 °C for the reaction with aldehydes, affording b-hydroxy esters (4) of high optical purity (90-96% ee) upon hydrolytic workup. Byproducts are insoluble cyclopentadienyltitanium oxides (5) and the ligand diacetone-glucose (DAGOH, 6). The oxides (5) can be separated by filtration and may be recycled to CpTiCl3. Ligand (6) and product are either separated by conventional methods (crystallization, distillation, chromatography), or glucose is extracted into the aqueous phase after acetonide cleavage in 0.1 N HCl (1.5 h at rt).1a,b In the case of isovaleraldehyde (R = i-Bu) it could be shown that the enantioselectivity (92-96% ee) is retained up to rt (27 °C).1a,b

A clear drawback of this reagent is the availability of only one enantiomer, the one favoring the re attack to the aldehyde carbonyl, as only D-glucose is readily available. si Attack is observed with the analogous enolate prepared from Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium, but only with moderate enantioselectivity (78% ee).1c,6 The reagent (2) is probably the most versatile chirally modified acetate enolate. Good results have also been obtained with the Mg enolate of 2-acetoxy-1,1,2-triphenylethanol7 and with boron enolates derived from 2,4-dialkylborolanes.8 Chiral Fe-acetyl complexes, which can be considered as acetate equivalents, give impressive stereocontrol upon enolization and aldol reaction.9 Except for unsaturated residues R, b-hydroxy esters (4) of excellent optical purity can also be obtained by enantioselective hydrogenation of the corresponding b-keto esters catalyzed by RuCl2(BINAP).10

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in Et2O,11 was chosen.2 Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at -78 °C. The completion of this step is evident by the disappearance of racemic anti-aldol (9) in favor of optically active syn-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anti-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This anti-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative (E)-titanium enolate derived from (7), is warmed for 4-5 h to -30 °C before reaction with an aldehyde (RCHO) again at -78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of syn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = t-Bu) are sluggish at -78 °C and have therefore been carried out at -50 to -30 °C.

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones,12 a-siloxy ketones,13 boron enolates with chiral ligands,14 as well as tin enolates.15 Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of O-silyl ketene acetals.16 Most of these reactions afford syn-aldols; good methods for the anti-isomers have only become available recently.8,17

Transmetalation of the (E)-O-Li-enolate derived from the stabase-protected glycine ethyl ester (11) with 1.1 equiv of (1) affords the chiral Ti enolate (12), which adds with high re selectivity to various aldehydes.3,18 By mild acidic cleavage of the silyl protecting group, the primary product (13) can be transformed to various N-derivatives (14) of D-threo-a-amino-b-hydroxy acids in 45-66% yield and with excellent enantio- and syn(threo) selectivity (97-99%) (eq 3). An exception with lower enantioselectivity is glyoxylic ester (ethyl ester 78% ee; t-butyl ester 87% ee).

In this case the enantiomers are available by the analogous conversion of glycine t-butyl ester using Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium. An elegant alternative is the enantioselective addition of isocyanoacetate to aldehydes under the catalysis of a chiral AuI complex.19 Further methods, also for the anti(erythro) epimers, can be found in recent reviews of enantioselective a-amino acid synthesis.20

Allyltitanation of Aldehydes.

The allyltitanium complex (15) is obtained by reaction of chloride (1) (1.1 equiv) with allylmagnesium chloride in Et2O for 1 h at 0 °C.4 The compound (15) has been characterized by 13C NMR.5 Reaction with various aldehydes (RCHO) at -78 °C and hydrolysis affords the homoallyl alcohols (16) (55-88%) of high optical purity (85-94% ee) (eq 4).4 The isolation of the product is analogous to the aldol reactions (cf. eq 1).

The enantiomers of (16) are obtained analogously by using Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium.21 The stereoselectivity of this cyclic Ti complex in allyltitanations is better than the diacetone-glucose system (1). It is therefore advisable to use the (4S,trans) enantiomer instead of (1) for controlling the re addition to problematic substrates. For further examples of this method and for analogous reagents see the discussion provided in Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium.

1. (a) Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker, M. AG(E), 1989, 28, 495. (b) Oertle, K.; Beyeler, H.; Duthaler, R. O.; Lottenbach, W.; Riediker, M.; Steiner, E. HCA 1990, 73, 353. (c) Cambie, R. C.; Coddington, J. M.; Milbank, J. B. J.; Paulser, M. G.; Rustenhoven, J. J.; Rutledge, P. S.; Shaw, G. L.; Sinkovich, P. I. AJC 1993, 46, 583.
2. Duthaler, R. O.; Herold, P.; Wyler-Helfer, S.; Riediker, M. HCA 1990, 73, 659.
3. Bold, G.; Duthaler, R. O.; Riediker, M. AG(E) 1989, 28, 497.
4. Riediker, M.; Duthaler, R. O. AG(E) 1989, 28, 494.
5. Riediker, M.; Hafner, A.; Piantini, U.; Rihs, G.; Togni, A. AG(E) 1989, 28, 499.
6. Duthaler, R. O.; Hafner, A.; Riediker, M. PAC 1990, 62, 631.
7. Braun, M. AG(E) 1987, 26, 24.
8. (a) Masamune, S.; Sato, T.; Kim, B. M.; Wollmann, T. A. JACS 1986, 108, 8279. (b) Reetz, M. T.; Rivadeneira, E.; Niemeyer, C. TL 1990, 31, 3863.
9. (a) Liebeskind, L. S.; Welker, M. E. TL 1984, 25, 4341. (b) Davies, S. G.; Dordor, I. M.; Warner, P. CC 1984, 956. (c) Brunner, H. AG 1991, 103, A310.
10. Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa, S. JACS 1987, 109, 5856.
11. Montgomery, S. H.; Pirrung, M. C.; Heathcock, C. H. OS 1985, 63, 99.
12. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
13. (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. AG(E) 1985, 24, 1. (b) Heathcock, C. H. Aldrichim. Acta 1990, 23, 99.
14. (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. JACS 1989, 111, 5493. (b) Corey, E. J.; Kim, S. S. JACS 1990, 112, 4976.
15. Mukaiyama, T.; Kobayashi, S.; Sano, T. T 1990, 46, 4653.
16. (a) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. JACS 1991, 113, 4247. (b) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. T 1993, 49, 1761.
17. (a) Helmchen, G.; Leikauf, U.; Taufer-Knöpfel, I. AG(E) 1985, 24, 874. (b) Gennari, C.; Schimperna, G.; Venturini, I. T 1988, 44, 4221. (c) Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G.; TL 1991, 32, 61. (d) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. JOC 1991, 56, 2499. (e) Myers, A. G.; Widdowson, K. L.; Kukkola, P. J. JACS 1992, 114, 2765. (f) Cardani, S.; De Toma, C.; Gennari, C.; Scolastico, C. T 1992, 48, 5557. (g) Oppolzer, W.; Lienard, P. TL 1993, 34, 4321.
18. Bold, G.; Allmendinger, T.; Herold, P.; Moesch, L.; Schär, H.-P.; Duthaler, R. O. HCA 1992, 75, 865.
19. Ito, Y.; Sawamura, M.; Hayashi, T. JACS 1986, 108, 6405.
20. (a) Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford, 1989. (b) Duthaler, R. O. T 1994, 50, 1539.
21. Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. JACS 1992, 114, 2321.

Andreas Hafner

Ciba-Geigy, Marly, Switzerland

Rudolf O. Duthaler

Ciba-Geigy, Basel, Switzerland

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